Modified drugs for use in liposomal nanoparticles

Abstract

Drug derivatives are provided herein which are suitable for loading into liposomal nanoparticle carriers. In some preferred aspects, the derivatives comprise a poorly water-soluble drug derivatized with a weak-base moiety that facilitates active loading of the drug through a LN transmembrane pH or ion gradient into the aqueous interior of the LN. The weak-base moiety can optionally comprise a lipophilic domain that facilitates active loading of the drug to the inner monolayer of the liposomal membrane. Advantageously, LN formulations of the drug derivatives exhibit improved solubility, reduced toxicity, enhanced efficacy, and/or other benefits relative to the corresponding free drugs.

What is claimed: 
     
       1. A pharmaceutical formulation comprising a liposomal nanoparticle having an interior compartment, wherein the interior compartment contains a docetaxel derivative having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein —C(═O)-(Spacer)-[N] is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       2. The formulation of  claim 1 , wherein the liposomal nanoparticle comprises a phosphatidylcholine containing saturated C 14 -C 22  carbon chains. 
     
     
       3. The formulation of  claim 2 , wherein the liposomal nanoparticle further comprises a sterol. 
     
     
       4. The formulation of  claim 3 , wherein the liposomal nanoparticle comprises the sterol and the phosphatidylcholine in a molar ratio of from 0.1:1 to 1:1. 
     
     
       5. The formulation of  claim 1 , wherein the interior compartment comprises an aqueous, low pH buffer. 
     
     
       6. The formulation of  claim 5 , wherein the low pH buffer comprises citrate. 
     
     
       7. The formulation of  claim 1 , wherein the interior compartment comprises an aqueous solution containing an ionophore selected from the group consisting of nigericin and A23187. 
     
     
       8. The formulation of  claim 1 , wherein the interior compartment comprises an aqueous solution containing ammonium sulfate. 
     
     
       9. The formulation of  claim 1 , wherein the ratio of the docetaxel derivative to the lipids in the liposomal nanoparticle is from about 0.01:1 to about 10:1 by weight. 
     
     
       10. The formulation of  claim 1 , wherein the lipid concentration of the formulation is from about 0.5 mg/mL to about 100 mg/mL. 
     
     
       11. The formulation of  claim 10 , wherein the lipid concentration is from about 10 mg/mL to about 50 mg/mL. 
     
     
       12. The formulation of  claim 1 , wherein the liposomal nanoparticle is less than about 0.05 microns in size. 
     
     
       13. The formulation of  claim 1 , wherein the liposomal nanoparticle is between about 0.1 and 0.5 microns in size. 
     
     
       14. The formulation of  claim 1 , wherein the liposomal nanoparticle is suspended in an aqueous external medium. 
     
     
       15. The formulation of  claim 1 , further comprising one or more substances selected from the group consisting of a pH adjusting agent, a buffering agent, a tonicity adjusting agent, a free radical quencher, and an antioxidant. 
     
     
       16. The formulation of  claim 1 , wherein the formulation is lyophilized. 
     
     
       17. The formulation of  claim 1 , wherein the formulation is sterilized. 
     
     
       18. The formulation of  claim 1 , wherein the liposomal nanoparticle has an in vivo release half-life of between about 1 to about 96 hours. 
     
     
       19. The formulation of  claim 1 , wherein:
 the liposomal nanoparticle is between about 0.1 and 0.5 microns in size; 
 the liposomal nanoparticle comprises a sterol and a phosphatidylcholine in a molar ratio of from 0.1:1 to 1:1, the phosphatidylcholine containing saturated C 14 -C 22  carbon chains; 
 the interior compartment comprises an aqueous, low-pH citrate buffer; 
 the liposomal nanoparticle is suspended in an aqueous external medium; 
 the lipid concentration of the formulation is from about 10 mg/mL to about 50 mg/mL; and 
 the ratio of the docetaxel derivative to the lipids in the liposomal nanoparticle is from about 0.01:1 to about 10:1 by weight. 
 
     
     
       20. The formulation of  claim 1 , wherein the docetaxel derivative has the structure: 
       
         
           
           
               
               
           
         
       
     
     
       21. The formulation of  claim 19 , wherein the docetaxel derivative has the structure: